Who, What, When, Where, Why: Why the 5 W’s Matter When Taking Your Medication

By Shanum Sheza Dewan

Oftentimes, we forget to take our medication. To compensate for this, we may take our medication later in the day. However, simply taking your medication at any point during the day may have adverse consequences. 

For example, let’s picture these two scenarios: 

1. A person taking cholesterol medicine with grapefruit juice.

2. A person taking Acetaminophen before going out for a drink. 

Each of these scenarios has inadvertently created a drug interaction that may lead to serious complications, such as kidney failure, liver damage, and internal bleeding (TED-Ed, 2019). Drug interactions are defined as the combination of a drug with a different substance, whereby the effects are not the normal effects of the drug or substance if they were consumed separately. 

In addition to two or more drugs being consumed simultaneously, there are also drug-food interactions. Drug-food interactions are defined as a reaction between the drug and the food or beverage. Drug-food interactions can occur with both prescriptions and over-the-counter medications (Bushra et al., 2011, 77-83). Examples of drug-food interactions are the first two scenarios, where Person A is taking cholesterol medicine with grapefruit juice and Person B is taking Acetaminophen and alcohol. 

Scenario 1: Cholesterol Medicine and Grapefruit Juice 

Generally, the rule is if you consume a substantial volume of grapefruit juice, whilst taking a certain cholesterol-lowering statin drug, too much of the drug remains in your body. 

Approximately fifty percent of marketed drugs are metabolized through the essential enzyme called CYP3A4 (Teo et al., 2015, 241-53). Grapefruit juice contains chemicals called furanocoumarins. Furanoocoumarins is a substance that comes from certain plants and is found in citrus fruits, such as grapefruits, Seville oranges, pomelos, and limes. Although citrus fruits have health benefits, furanocoumarins can affect how certain enzymes in the liver and the small intestine break down drugs (National Cancer Institute, 1937). Grapefruit juice can block the action of intestinal CYP3A4. So instead of being metabolized, there is an increase in the concentration of the drug in your body. 

In 2009, atorvastatin (Lipitor) was, in fact, the most widely prescribed brand-name drug in the United States of America, with more than 42 million prescriptions at a total retail cost exceeding $5 billion. Therefore, understanding the probability of clinically significant interaction of atorvastatin with Grapefruit Juice and the consequences of an interaction if it did happen, is of general, medical, and public health importance (Reddy et al., 2011, 431-441).

In 2011, hyperlipidemia adult patients (who were at least 21 years old and were able to provide informed consent before enrollment) underwent treatment at the Watson Clinic, Lakeland, Florida, USA for a study. In this randomized trial, there were two groups of patients: Arm A patients, who continued their usual maintenance of atorvastatin doses of 10, 20, or 40mg, and Arm B patients, who used only half of their regular atorvastatin dose of 5, 10, or 20mg. Both Arm A patients and Arm B patients administered a single dose of Lipitor atorvastatin whilst also consuming 300 ml Grapefruit Juice every morning (Reddy et al., 2011, 431-441).

For every thirty days in the ninety-day trial period, the researchers measured lipid profiles, serum atorvastatin concentration, liver function tests, Creatine phosphokinase (CPK), and quality of life. By the end of the study, the following observations were ascertained: 

Results from Arm A Patients	Results from Arm B patients
The addition of consuming Grapefruit Juice daily during the morning period increased the median serum atorvastatin concentration between 19% to 26% compared to baseline levels taken on day 0.  However, when placed into wider context the increase of atorvastatin serum concentration was small, consequently there was negligible evidence between muscle toxicity and elevated risk of liver toxicity.	The addition of consuming Grapefruit Juice daily during the morning period decreased the media serum atorvastatin concentration between 12% to 25% compared to the day 0 baseline.  Once again, like in Arm A’s patients there was no evidence of muscle toxicity and elevated risk of liver toxicity

Although the study may not demonstrate a correlation between consuming 300 ml of Grapefruit Juice daily whilst taking cardiovascular medication and elevated risk of muscle and liver toxicity; it is crucial to remember that in the study the consumption of Grapefruit Juice was moderated. The NHS states that drinking lots of grapefruit juice (more than about a liter a day) can affect the way atorvastatin medication works (NHS, 2022).

Scenario 2: Acetaminophen and Alcohol 

The National Cancer Institute has defined Acetaminophen as a drug that reduces pain and fever (but not inflammation). It belongs to the family of drugs called analgesics (National Cancer Institute, 1937). Alcohol is defined as a chemical substance found in drinks such as beer, wine, and liquor (National Cancer Institute, 1937). However, there have been many reports claiming that the hepatotoxicity of paracetamol (acetaminophen) is increased in chronic alcoholics and that such individuals not only carry an increased risk of severe and fatal liver damage after acute “therapeutic” use (Prescott, 2000, 291-301). The paracetamol-alcohol interaction is complex, however, to put it simply, paracetamol was found to cause liver damage through conversion by hepatic cytochrome P450 enzymes to a minor but toxic intermediate metabolite, and this was subsequently identified as N-acetyl-p-benzoquinone (Prescott, 2000, 291-301). Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis (Zhao et al., 2021, 12808). CYPs are also capable of affecting drug response by influencing drug action, safety, bioavailable, and drug resistance through metabolism, in both metabolic organs and local sites of action. Therefore, when P450 catalyzes the drug interaction between acetaminophen and alcohol the metabolite of acetaminophen, named N-acetyl-p-benzoquinone imine (NAPQI) is produced (Dahlin et al., 1984, 1327-1331). 

The significance of educating the public regarding common drug interactions can: 

• Decrease the incidence rate of serious health complications regarding drug interactions 

• Encourages medical practitioners to look at the drug currently being administered when prescribing any new medication 

• Decreases the mortality rate of patients, where the primary cause of death was aggregated drug interactions 

• Increases the effectiveness of drugs in the body, for patients being administered several different drugs regularly 

Although drug interactions have established a reputation for being negative, in hindsight some drug interactions can bring about positive effects. Research into drug interactions has provided the Pharmaceutical, Medical, Public Health, and other Healthcare-associated fields to educate themselves and the public about the necessary precautions when taking their medication. Indeed, there are drug interactions that are yet to be studied, for example, drug-drug interactions whereby patients are regularly administering more than two medications in the same period. Drug interactions provide scientists the opportunity to find new effects of drugs that neither of them has alone, but together instead of causing a side effect, they could be a new and novel treatment for diseases that do not have treatment or for diseases where treatments are not effective (TED-MED, 2016). So, the next time you take your medication remember the 5 W's. 

References

Bushra, R., Aslam, N., & Khan, A. Y. (2011). Food-Drug interactions. Oman Med J, 26(2), 77-83. PubMed Central. Retrieved August 29, 2024, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191675/

Dahlin, D. C., Miwa, G. T., Lu, A. Y., & Nelson, S. D. (1984). N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci U S A., 81(5), 1327-1331. PubMed Central. Retrieved August 29, 2024, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC344826/?page=1

National Cancer Institute. (1937). Acetaminophen. National Cancer Institute. Retrieved August 29, 2024, from https://www.cancer.gov/publications/dictionaries/cancer-terms/def/acetaminophen

National Cancer Institute. (1937). Alcohol. National Cancer Institute. Retrieved August 29, 2024, from https://www.cancer.gov/search/results?swKeyword=alcohol

National Cancer Institute. (1937). Furanocoumarin. National Cancer Institue. Retrieved August 29, 2024, from https://www.cancer.gov/publications/dictionaries/cancer-terms/def/furanocoumarin

NHS. (2022, March 7). Common questions about atorvastatin. NHS. Retrieved August 29, 2029, from https://www.nhs.uk/medicines/atorvastatin/common-questions-about-atorvastatin/#:~:text=It%27s%20best%20not%20to%20have,of%20you%20having%20side%20effects

Prescott, L. F. (2000). Paracetamol, alcohol and the liver. Br J Clin Pharmacol, 49(4), 291-301. PubMed Central. Retrieved August 29, 2024, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014937/

Reddy, P., Ellington, D., Zhu, Y., Zdrojewski, I., Parent, S. J., Harmatz, J. S., Derendorf, H., Greenblatt, D. J., & Browne, Jr, K. (2011). Serum concentrations and clinical effects of atorvastatin in patients taking grapefruit juice daily. Br J Clin Pharmacol, 72(3), 434-441. PubMed Central. Retrieved August 29, 2024, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175512/#b13

TED-Ed. (2019, November 12). The dangers of mixing drugs. TED-Ed - The dangers of mixing drugs. Retrieved August 29, 2024, from https://www.youtube.com/watch?v=aDsW8tx1KsY&t=45s

TED-MED. (2016, May 23). What really happens when you mix drugs. TED-MED. Retrieved August 29, 2024, from https://www.youtube.com/watch?v=avuhY7D71sQ

Teo, Y. L., Ho, H. K., & Chan, A. (2015). Metabolism-related pharmacokinetic drug−drug interactions with tyrosine kinase inhibitors: current understanding, challenges and recommendations. Br J Clin Pharmacol, 79(2), 241-253. PubMed Central. Retrieved August 29, 2024, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309630/#:~:text=The%20main%20CYP%20enzyme%2C%20CYP3A4,activity%20of%20this%20metabolic%20pathway

Zhao, M., Ma, J., Li, M., Zhang, Y., Jiang, B., Zhao, X., Huai, C., Shen, L., Zhang, N., He, L., & Qin, S. (2021). Cytochrome P450 Enzymes and Drug Metabolism in Humans. Int J Mol Sci, 22(23), 12808. PubMed Central. Retrieved August 29, 2024, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657965/